SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Loperamide 2mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2mg loperamide hydrochloride.

Excipients: each tablet contains 100mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Light green coloured capsule shaped, biconvex uncoated tablets, plain on one side and score line on other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the symptomatic treatment of acute diarrhoea of any aetiology including acute exacerbations of chronic diarrhoea for periods of up to 5 days in adults and children over 6 years. For the symptomatic treatment of chronic diarrhoea in adults.

4.2    Posology and method of administration

ACUTE DIARRHOEA

Adults and children over 6 years of age:

Two tablets initially, followed by one tablet after each loose stool. The usual dose is 3-4 tablets a day. The total daily dose should not exceed 8 tablets.

Children between the ages of 2 and 5 years:

These tablets are not recommended for children between 2 and 5 years.An alternative formulation (Oral solution/liquid) of Loperamide suitable for children should be administered in this patient population.

Children under 2 years of age:

Loperamide is contraindicated in children under 2 years of age.

CHRONIC DIARRHOEA

Adults:

Studies have shown that patients may need widely differing amounts of loperamide. The starting dose should be between two and four tablets per day in divided doses, depending on severity. If required, this dose can be adjusted according to result up to a maximum of eight tablets daily.

Having established the patient's daily maintenance dose, the tablets may be administered on a twice daily regimen. Tolerance has not been observed and therefore subsequent dosage adjustment should be unnecessary.

USE IN ELDERLY

No dose adjustment is required for the elderly.

RENAL IMPAIRMENT

No dose adjustment is required for patients with renal impairment.

HEPATIC IMPAIRMENT

Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide 2mg Tablets should be used with caution in such patients because of reduced first pass metabolism (see 4.4 Special warnings and precautions for use).

Method of administration Oral use.

4.3 Contraindications

Loperamide 2mg Tablets are contraindicated in:

•    patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

•    children less than 6 years of age.

•    when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon, in particular:

Loperamide hydrochloride must be discontinued promptly when ileus or constipation are present or when abdominal distension develops, particularly in severely dehydrated children,

-    in patients with acute ulcerative colitis,

-    in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter,

-    in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Loperamide 2mg Tablets should not be used alone in acute dysentery, which is characterised by blood in stools and elevated body temperatures.

4.4 Special warnings and precautions for use

Treatment of diarrhoea with Loperamide is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of Loperamide 2mg Tablets does not preclude the administration of appropriate fluid and electrolyte replacement therapy. Since persistent diarrhoea can be an indicator of potentially more serious conditions, Loperamide 2mg Tablets should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

Loperamide HCl should not be given to children aged 2 to 6 years of age without medical prescription and supervision. Loperamide 2mg Tablets must be used with caution when the hepatic function necessary for the drug's metabolism is defective (eg in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Patients with AIDS treated with Loperamide 2mg Tablets for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.

In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of Loperamide hydrochloride should be discontinued and patients should be advised to consult their physician.

Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism.

4.5 Interaction with other medicinal products and other forms of interaction

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages (2 mg, up to 16 mg maximum daily dose), is unknown.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e. subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

The results of one published pharmacokinetic study suggested that the concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations presumably due to slower gastrointestinal motility, although no clinical effects were reported.

It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

4.6 Fertility, pregnancy and lactation

Safety in human pregnancy has not been established although studies in animals have not demonstrated any teratogenic effects or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before loperamide HCl is given during pregnancy, especially during the first trimester. As with other drugs, it is not advisable administer Loperamide 2mg Tablets in pregnancy.

Small amounts of loperamide may appear in human breast milk. Therefore, Loperamide 2mg Tablets is not recommended during breast-feeding.

Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects on ability to drive and use machines

Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes when diarrhoea is treated with Loperamide 2mg Tablets. Therefore, it is advisable to use caution when driving a car or operating machinery. See section 4.8 Undesirable Effects.

Undesirable effects

The safety of loperamide HCl was evaluated in 3076 adults and children aged >12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide HCl used for the treatment of diarrhoea. Of these, 26 trials were in acute diarrhoea (N=2755) and 5 trials were in chronic diarrhoea (N=321).

The most commonly reported (i.e., >1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide HCl in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%). In clinical trials in chronic diarrhoea, the most commonly reported (i.e., >1% incidence) ADRs were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (in acute or chronic diarrhoea or both) or post-marketing experience.

The frequency categories use the following convention: very common (> 1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); and very rare (<1/10,000).

System Organ Class	Indication
	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)	Acute + Chronic Diarrhoea and postmarketing experience
Immune System Disorders Hypersensitivity reaction3, Anaphylactic reaction (including Anaphylactic shock)*1, Anaphylactoid reaction*1			Rare
Nervous System Disorders Headache Dizziness Somnolence*1 Loss of consciousness*1, Stupor*1, Depressed level of consciousness*1, Hypertonia*1, Coordination abnormality*1	Common Uncommon	Uncommon Common	Common Common Uncommon Rare
Eye Disorders Miosis*1			Rare
Gastrointestinal Disorders Constipation, Nausea, Flatulence Abdominal pain, Abdominal discomfort, Dry mouth Abdominal pain upper, Vomiting Dyspepsia Ileus*1 (including paralytic ileus), Megacolona (including toxic megacolonb), Abdominal distension, Glossodynia	Common Uncommon Uncommon Rare	Common Uncommon Uncommon	Common Uncommon Uncommon Uncommon Rare Rare
Skin and Subcutaneous Tissue Disorders Rash	Uncommon		Uncommon
Skin and Subcutaneous Tissue Disorders Bullous eruption*1 (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Angioedemaa, Urticaria*1, Pruritus*1			Rare
Renal and Urinary Disorders Urinary retention*1			Rare
General Disorders and Administration Site Conditions Fatigue*1			Rare

a: Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl combined, including trials in children <12 years (N=3683). b: See section 4.4 Special Warnings and Special Precautions for use.

c: Reported for the orodispersible tablet only.

For clinical trial ADRs where no frequency is presented, the term was not observed or considered an ADR for this indication.

Paediatric population

The safety of loperamide HCl was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials of loperamide HCl used for the treatment of acute diarrhoea. In general, the ADR profile in this patient population was similar to that seen in clinical trials of loperamide HCl in adults and children aged 12 years and over.

4.9 Overdose

Symptoms

In case of overdose the following effects may be observed (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, respiratory depression) constipation, urinary retention, ileus and neurological symptoms (miosis, muscular hypertonia, somnolence and bradypnoea). Children may be more sensitive to CNS effects than adults.

Treatment

If intoxication is suspected, naloxone may be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated, the patient should be kept under constant observation for at least 48 hours in order to detect any possible depression of the central nervous system. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects. Gastric lavage, or induced emesis and or enema or laxatives may be recommended.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipropulsives, ATC code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic properties

The half-life of loperamide in man is 10.8 hours with a range of 9-14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

5.3 Preclinical safety data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate

Maize starch Talc

Magnesium stearate Povidone

Brilliant Blue (E133)

Quinoline Yellow (E104)

Colloidal anhydrous silica Sodium starch glycolate

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions    for storage

This medicine product does not require any special storage instructions.

6.5    Nature and contents of container

Blisters composed of PVC/PVDC film, which is clear, non-toxic, transparent and thermoformable and of aluminium foil.

Pack size: 30 tablets.

Not all pack sizes may be marketed

6.6    Special precautions    for disposal

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Marketing Authorisation Holder:

Morningside Healthcare Limited 115 Narborough Road Leicester, LE3 0PA United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0087

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 25/02/2011

10 DATE OF REVISION OF THE TEXT

19/11/2012